Modulating Stress Granules via HDAC6 Inhibition: A Promising Strategy against Alzheimer's Disease

Emerging evidence suggests that dysregulated cellular stress responses, particularly the formation and persistence of stress granules (SGs), may significantly contribute to Alzheimer's disease (AD) pathogenesis. SGs are dynamic, membrane-less ribonucleoprotein assemblies that sequester stalled translation preinitiation complexes during cellular stress. Under physiological conditions, SGs are transient and disassemble upon stress resolution, often facilitated by heat shock proteins (HSPs). However, under chronic stress, persistent or aberrant SGs can form, which may seed pathological protein aggregation and exacerbate proteostatic imbalance, neuroinflammation, and neurodegeneration. Despite the growing body of evidence linking HDAC6 to SG dynamics and AD pathology, the precise mechanistic relationship remains unresolved. This review highlights the current understanding of HDAC6-mediated SG regulation in AD, identifies critical knowledge gaps, and discusses the therapeutic potential of selective HDAC6 inhibition in modulating SG pathology and neuroinflammation.